Functional Specialization of the Mediator-Associated Kinases CDK8 and CDK19

University Of Colorado At Boulder, Boulder CO

Investigators

Abstract

Intellectual Merit: A major challenge in modern biology is to elucidate the molecular mechanisms employed by cells to regulate expression of thousands of genes in various contexts. Accurate regulation of gene activity is a key element of every major biological process. Specialized protein machineries regulate gene activity by decoding the information carried in DNA to satisfy the ever-changing needs of the cell. One such protein complex, known as Mediator, is recognized as a critical regulator of gene activity from yeast to humans, yet little is known about its mechanism of action. This research project investigates the function of two proteins within the Mediator complex, CDK8 and CDK19. Preliminary results demonstrate that CDK8 and CDK19 regulate the activity of different groups of genes involved in diverse cellular functions. This project aims to define the molecular mechanisms by which CDK8 and CDK19 enable cells to adjust the activity of different gene sets in response to changes in the cellular environment. This research is expected to have a transformative impact on the understanding of Mediator in particular and the evolution of gene expression control mechanisms in general. Given the quasi-universal role of Mediator in the control of gene activity, the discoveries arising from this project will have far reaching implications in the fields of cellular and molecular biology. Moreover, the innovative techniques developed in this project for the study of Mediator in human cells will produce a positive ripple effect in the gene expression field by enabling similar studies of other gene regulators. Broader Impacts: This project is carried out by a teaching-research team that strongly promotes science education and diversity in academia. This collaborative team involves trainees at the undergraduate, graduate and post-doctoral levels who work in an environment displaying gender balance and inclusion of minorities. Both the host institution and the Principal Investigator participate actively in programs that aim to: a) increase the number of minority students earning PhDs, b) provide hands-on research experience to undergraduates, c) prepare undergraduate students to pursue PhDs in the biosciences, and d) increase the representation of women in leadership positions in academia. The success of these endeavors is documented by multiple undergraduate authors in the high impact publications from this laboratory and by the fact that most of the 30+ undergraduates trained in this group have advanced to graduate school, medical school or teaching positions. The Principal Investigator is an active member of the local Hispanic community and a recognized life science educator at the University of Colorado at Boulder, where he is the Instructor of a large undergraduate course and co-Instructor of several graduate courses. Members of this team promote scientific literacy in the public via regular contributions to the popular press and outreach activities at the state and national level.